Abnormal Development - Developmental Origins of Health and Disease

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Introduction

Normal distribution curve on graph
Normal distribution curve (red)

Environmental derived abnormalities relate to maternal lifestyle, environment and nutrition and while some of these directly effect embryonic development, there is also growing evidence that some effects are more subtle and relate to later life health events.


This theory, now called "developmental origins of health and disease" (DOHAD or DOHaD) and also previously Fetal Origins Hypothesis, is based on the early statistical analysis carried out by David Barker (1938 - 2013) of low birth weight data collected in the early 1900's in the south east of England which he then compared with these same babies later health outcomes. The theory was therefore originally called the "Barker Hypothesis" and has recently been renamed as "fetal origins" or "programming". Several origins have been suggested including: fetal undernutrition, endocrine (increased cortisol exposure), genetic susceptibility and accelerated postnatal growth.


More recently, discussion has occurred relating to how the data is both collected and analyzed, suggesting perhaps a smaller effect than original research suggested (see Lucas reference). Statistical methodology aside, these studies long-term periods of accurate data collection and we may have to wait some time for this research to develop.


Some research has now shifted from birth weight emphasis to that of the early postnatal infant growth. (More? Postnatal - Growth Charts)


Abnormality Links: Introduction | Genetic | Environmental | Unknown | Teratogens | Ectopic Implantation | Cardiovascular | Coelomic Cavity | Endocrine | Gastrointestinal Tract | Genital | Head | Integumentary | Musculoskeletal | Limb | Neural | Neural Crest | Renal | Respiratory | Placenta | Sensory | Hearing | Vision | Twinning | Developmental Origins of Health and Disease | ICD-10
Historic Embryology  
1915 Congenital Cardiac Disease | 1917 Frequency of Anomalies in Human Embryos | 1920 Hydatiform Degeneration Tubal Pregnancy | 1921 Anencephalic Embryo
| Birth-Weight

Some Recent Findings

  • DOHAD2017 10th anniversary World Congress in Rotterdam.
  • Delivery of a small for gestational age infant and greater maternal risk of ischemic heart disease[1] "Delivery of a small for gestational age (SGA) infant has been associated with increased maternal risk of ischemic heart disease (IHD). ...Risk of maternal IHD was evaluated in a population based cross-sectional study of 6,608 women with a prior live term birth who participated in the National Health and Nutrition Examination Survey (1999-2006), a probability sample of the U.S. population....Giving birth to a SGA infant is strongly and independently associated with IHD and a potential risk factor that precedes IHD by decades. A pregnancy that produces a SGA infant may induce long-term cardiovascular changes that increase risk for IHD." (Note this paper refers to a Maternal not Neonatal Risk).
  • Fetal origins of adult diabetes[2] "According to the fetal origin of adult diseases hypothesis, the intrauterine environment through developmental plasticity may permanently influence long-term health and disease. Therefore, intrauterine growth restriction (IUGR), due either to maternal, placental, or genetic factors, may permanently alter the endocrine-metabolic status of the fetus, driving an insulin resistance state that can promote survival at the short term but that facilitates the development of type 2 diabetes mellitus and metabolic syndrome in adult life, especially when the intrauterine nutrient restriction is followed by a postnatal obesogenic environment."
  • Perinatal Risk Factors for Diabetes in Later Life[3] "Low birth weight is consistently associated with an increased risk of non-insulin dependent diabetes mellitus in adulthood, but the individual contributions from poor fetal growth and preterm birth are not known. ....Our results suggest that the association between low birth weight and diabetes is due to factors associated with both poor fetal growth and short gestational age."
  • Persistent epigenetic differences associated with prenatal exposure to famine in humans[4] "Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944-45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks." (More? see also Molecular Development - Epigenetics)
  • The fetal origins hypothesis—10 years on (2005)[5]"In 1995 David Barker wrote: “The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease.”1 Now, 10 years later, the importance of events before birth for lifetime health has been confirmed in many populations."
More recent papers
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Developmental Origins of Health and Disease

Philippe de Medina Xenohormesis in early life: New avenues of research to explore anti-aging strategies through the maternal diet. Med. Hypotheses: 2017, 109;126-130 PubMed 29150271

Martine Armand, Jonathan Y Bernard, Anne Forhan, Barbara Heude, Marie-Aline Charles, EDEN mother-child cohort study group Maternal nutritional determinants of colostrum fatty acids in the EDEN mother-child cohort. Clin Nutr: 2017; PubMed 29146525

A Qasim, M Turcotte, R J de Souza, M C Samaan, D Champredon, J Dushoff, J R Speakman, D Meyre On the origin of obesity: identifying the biological, environmental and cultural drivers of genetic risk among human populations. Obes Rev: 2017; PubMed 29144594

Darren L Dahly, Xia Li, Hazel A Smith, Ali S Khashan, Deirdre M Murray, Mairead E Kiely, Jonathan O'B Hourihane, Fergus P McCarthy, Louise C Kenny, Patricia M Kearney Associations between maternal lifestyle factors and neonatal body composition in the Screening for Pregnancy Endpoints (Cork) cohort study. Int J Epidemiol: 2017; PubMed 29136159

Lindsey S Treviño, Tiffany A Katz Endocrine Disruptors and Developmental Origins of Nonalcoholic Fatty Liver Disease. Endocrinology: 2017; PubMed 29126168

Barker Hypothesis

David Barker (1938 - 2013)

There were some key papers by David Barker that initially studied UK birth weight data that gave rise to this area of research.[6][7][8]

“The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease.”


See also Fetal origins of adult disease-the hypothesis revisited.[9]

  • The hypothesis that adult disease has fetal origins is plausible, but much supportive evidence is flawed by incomplete and incorrect statistical interpretation.
  • When size in early life is related to later health outcomes only after adjustment for current size, it is probably the change in size between these points (postnatal centile crossing) rather than fetal biology that is implicated.
  • Even when birth size is directly related to later outcome, some studies fail to explore whether this is partly or wholly explained by postnatal rather that prenatal factors.
  • These considerations are critical to understanding the biology and timing of "programming," the direction of future research, and future public health interventions.

David Barker (1938 - 2013)

Professor David Barker FRS, born 29 June 1938; died 27 August 2013.


"David Barker was one of the most influential clinical epidemiologists of our time. He challenged the idea that chronic disorders such as diabetes and cardiovascular disease are explained only by bad genes and unhealthy adult lifestyles. His 'Barker hypothesis' proposed that the fetal environment and early infant health permanently programme the body's metabolism and growth, and thus determine the pathologies of old age. Initially controversial, his ideas triggered an explosion of research worldwide into the relationship between early development and adult disease."[10]
"David Barker received the prestigious Richard Doll Prize in 2011 given by the International Epidemiology Association (IEA). This prize is given to a person who deserved to be a candidate for the Nobel Prize but would probably not be accepted by the Nobel Committee because of the way epidemiologic research is structured and conducted. In epidemiology we can seldom point towards a specific article or even a few articles or a single person who, by himself alone, changes the way we think."[11]


Links: memorial service

Fetal Growth Articles

Fetal growth.[12] "Recent epidemiological and experimental studies show that abnormal fetal growth can lead to serious complications, including stillbirth, perinatal morbidity and disorders extending well beyond the neonatal period. It is now clear that the intrauterine milieu is as important as genetic endowment in shaping the future health of the conceptus. Maternal characteristics such as weight, height, parity and ethnic group need to be adjusted for, and pathological factors such as smoking excluded, to establish appropriate standards and improve the distinction between what is normal and abnormal. Currently, the aetiology of growth restriction is not well understood and preventative measures are ineffective. Elective delivery remains the principal management option, which emphasizes the need for better screening techniques for the timely detection of intrauterine growth failure."

Fetal growth and long-term consequences in animal models of growth retardation.[13] "Perturbations of the maternal environment involve an abnormal intrauterine milieu for the developing fetus. The altered fuel supply (depends on substrate availability, placental transport of nutrients and uteroplacental blood flow) from mother to fetus induces alterations in the development of the fetal endocrine pancreas and adaptations of the fetal metabolism to the altered intrauterine environment, resulting in intrauterine growth retardation. The alterations induced by maternal diabetes or maternal malnutrition (protein-calorie or protein deprivation) have consequences for the offspring, persisting into adulthood and into the next generation."

Diabetes

Fetal origins of adult diabetes[14] "According to the fetal origin of adult diseases hypothesis, the intrauterine environment through developmental plasticity may permanently influence long-term health and disease. Therefore, intrauterine growth restriction (IUGR), due either to maternal, placental, or genetic factors, may permanently alter the endocrine-metabolic status of the fetus, driving an insulin resistance state that can promote survival at the short term but that facilitates the development of type 2 diabetes mellitus and metabolic syndrome in adult life, especially when the intrauterine nutrient restriction is followed by a postnatal obesogenic environment."

Perinatal Risk Factors for Diabetes in Later Life[15] "Low birth weight is consistently associated with an increased risk of non-insulin dependent diabetes mellitus in adulthood, but the individual contributions from poor fetal growth and preterm birth are not known. ....Our results suggest that the association between low birth weight and diabetes is due to factors associated with both poor fetal growth and short gestational age."

Renal

The Brenner hypothesis is a clinical hypothesis that states, individuals with a congenital reduction in nephron number have a much greater likelihood of developing adult hypertension and subsequent renal failure.[16] The hypothesis was developed in the 1980's by Barry Brenner a neurologist and researcher at the Brigham and Women's Hospital. This "congenital reduction" also fits with this DOHAD hypothesis.


Links: Renal System Development | Barry Brenner

Cardiovascular

Neural Effects

The hypothesis proposes influences cause permanent changes in embryo/fetus, low birth weight, predisposition to chronic disease in adult life. Malnutrition in utero affects brain development, "low birth weight" or intrauterine growth restricted babies fare less well on measures of mental development in later life studies compared low birth weight babies (<2500 g) with controls, show impairment in neuro developmental tests up to age 11.

Intelligence is a combination of genetic and environmental influences (relative contributions of which are not yet established) and may vary over lifespan.

(Modified Text from[17] Note the commment made by Emeritus Professor P Pharaoh "One caveat that should be borne in mind, concerns the tests that are used to assess cognitive function. What do these tests actually measure? Ideally they measure innate mental ability, whatever that is, at a point in time.")

In contrast, a recent study of only postnatal growth (to 3 years of age) identified "Slower infant weight gain was not associated with poorer neurodevelopmental outcomes in healthy, term-born 3-year-old children."[18]

NCBI Bookshelf

Resources available from online textbooks freely available at National Library of Medicine (USA), National Center for Biotechnology Information.

Health Services/Technology Assessment Text (HSTAT)

Evidence table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes Part I

Evidence table 5B. Studies Evaluating Association of LBW of Audiology Outcomes Part II

Birth Terms

  • Premature infant - An infant born before 37 weeks of estimated gestational age
  • Low birth weight - Birth weight < 2,500 g (5 lb, 8 oz)
  • Very low birth weight - Birth weight < 1,500 g (3 lb, 5 oz)
  • Extremely low birth weight - Birth weight < 1,000 g (2 lb, 3 oz)

References

  1. Radek Bukowski, Karen E Davis, Peter W F Wilson Delivery of a small for gestational age infant and greater maternal risk of ischemic heart disease. PLoS ONE: 2012, 7(3);e33047 PubMed 22431995 | PLoS One.
  2. Christina Kanaka-Gantenbein Fetal origins of adult diabetes. Ann. N. Y. Acad. Sci.: 2010, 1205;99-105 PubMed 20840260
  3. Magnus Kaijser, Anna-Karin Edstedt Bonamy, Olof Akre, Sven Cnattingius, Fredrik Granath, Mikael Norman, Anders Ekbom Perinatal risk factors for diabetes in later life. Diabetes: 2009, 58(3);523-6 PubMed 19066311
  4. Bastiaan T Heijmans, Elmar W Tobi, Aryeh D Stein, Hein Putter, Gerard J Blauw, Ezra S Susser, P Eline Slagboom, L H Lumey Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl. Acad. Sci. U.S.A.: 2008, 105(44);17046-9 PubMed 18955703
  5. Johan G Eriksson The fetal origins hypothesis--10 years on. BMJ: 2005, 330(7500);1096-7 PubMed 15891207
  6. D J Barker The fetal and infant origins of adult disease. BMJ: 1990, 301(6761);1111 PubMed 2252919
  7. D J Barker, C N Martyn The maternal and fetal origins of cardiovascular disease. J Epidemiol Community Health: 1992, 46(1);8-11 PubMed 1573367
  8. D J Barker Fetal nutrition and cardiovascular disease in later life. Br. Med. Bull.: 1997, 53(1);96-108 PubMed 9158287
  9. A Lucas, M S Fewtrell, T J Cole Fetal origins of adult disease-the hypothesis revisited. BMJ: 1999, 319(7204);245-9 PubMed 10417093 | BMJ
  10. Cyrus Cooper David Barker (1938-2013). Nature: 2013, 502(7471);304 PubMed 24132283
  11. K Holemans, L Aerts, F A Van Assche Fetal growth and long-term consequences in animal models of growth retardation. Eur. J. Obstet. Gynecol. Reprod. Biol.: 1998, 81(2);149-56 PubMed 9989859
  12. Christina Kanaka-Gantenbein Fetal origins of adult diabetes. Ann. N. Y. Acad. Sci.: 2010, 1205;99-105 PubMed 20840260
  13. Magnus Kaijser, Anna-Karin Edstedt Bonamy, Olof Akre, Sven Cnattingius, Fredrik Granath, Mikael Norman, Anders Ekbom Perinatal risk factors for diabetes in later life. Diabetes: 2009, 58(3);523-6 PubMed 19066311
  14. B M Brenner, D L Garcia, S Anderson Glomeruli and blood pressure. Less of one, more the other? Am. J. Hypertens.: 1988, 1(4 Pt 1);335-47 PubMed 3063284
  15. S D Shenkin, J M Starr, A Pattie, M A Rush, L J Whalley, I J Deary Birth weight and cognitive function at age 11 years: the Scottish Mental Survey 1932. Arch. Dis. Child.: 2001, 85(3);189-96 PubMed 11517097
  16. Mandy B Belfort, Sheryl L Rifas-Shiman, Janet W Rich-Edwards, Ken P Kleinman, Emily Oken, Matthew W Gillman Infant growth and child cognition at 3 years of age. Pediatrics: 2008, 122(3);e689-95 PubMed 18762504

Journal

  • Journal of Developmental Origins of Health and Disease JDOHaD publishes leading research in the field of developmental origins of health and disease (DOHaD), focusing on how the environment during early animal and human development, and interactions between environmental and genetic factors, influence health in later life and risk of disease. [jour PubMed listing]

Book Developmental origins of health and disease Reviewed by R L Boon Edited by Peter Gluckman, Mark Hanson. Published by Cambridge University Press, Cambridge, 2006, £85.00, pp 519. ISBN 0-521-84743-5

Reviews

Kara Calkins, Sherin U Devaskar Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care: 2011, 41(6);158-76 PubMed 21684471

J J Miranda Geelhoed, Vincent W V Jaddoe Early influences on cardiovascular and renal development. Eur. J. Epidemiol.: 2010, 25(10);677-92 PubMed 20872047

Christina Kanaka-Gantenbein Fetal origins of adult diabetes. Ann. N. Y. Acad. Sci.: 2010, 1205;99-105 PubMed 20840260

Bridget M Cota, Patricia Jackson Allen The developmental origins of health and disease hypothesis. Pediatr Nurs: 2010, 36(3);157-67 PubMed 20687308

Kellie L K Tamashiro, Timothy H Moran Perinatal environment and its influences on metabolic programming of offspring. Physiol. Behav.: 2010, 100(5);560-6 PubMed 20394764

Simon C Langley-Evans, Sarah McMullen Developmental origins of adult disease. Med Princ Pract: 2010, 19(2);87-98 PubMed 20134170

Pathik D Wadhwa, Claudia Buss, Sonja Entringer, James M Swanson Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin. Reprod. Med.: 2009, 27(5);358-68 PubMed 19711246


Articles

Dennis O Mook-Kanamori, Eric A P Steegers, Paul H Eilers, Hein Raat, Albert Hofman, Vincent W V Jaddoe Risk factors and outcomes associated with first-trimester fetal growth restriction. JAMA: 2010, 303(6);527-34 PubMed 20145229


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